Critical Reviews in Microbiology Critical Reviews in Microbiology, 2009; 35(4): 283–309 2009

REVIEW ARTICLE

Candida parapsilosis: a review of its epidemiology, pathogenesis, clinical aspects, typing and antimicrobial susceptibility

Eveline C. van Asbeck1,2, Karl V. Clemons1, David A. Stevens1

1Division of Infectious Diseases, Santa Clara Valley Medical Center, and California Institute for Medical Research, San Jose, CA 95128 USA and Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA 94305, and 2Eijkman-Winkler Institute for Medical and Clinical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands

Abstract The Candida parapsilosis family has emerged as a major opportunistic and nosocomial pathogen. It causes multifaceted pathology in immuno-compromised and normal hosts, notably low birth weight neonates. Its emergence may relate to an ability to colonize the skin, proliferate in glucose-containing solutions, and adhere to plastic. When clusters appear, determination of genetic relatedness among strains and identifica- tion of a common source are important. Its virulence appears associated with a capacity to produce biofilm and production of phospholipase and aspartyl protease. Further investigations of the host-pathogen inter- actions are needed. This review summarizes basic science, clinical and experimental information about C. parapsilosis. Keywords: Candida parapsilosis, epidermiology, strain differentiation, clinical aspects, pathogenesis,

For personal use only. antifungal susceptibility

Introduction The organism was first described in 1928 (Ashford 1928), and early reports of C. parapsilosis described the organ- Candida bloodstream infections (BSI) remain an ism as a relatively non-pathogenic yeast in the normal exceedingly common life-threatening fungal disease flora of healthy individuals that was of minor clinical and are now recognized as a major cause of hospital- significance (Weems 1992). Important factors that have acquired infection (Douglas 2003; Tortorano et al. 2006; contributed to the increasing incidence of C. parapsilo- Tortorano et al. 2004). It is now the fourth most common sis are the use of life support systems, such as parenteral organism recovered from blood cultures among hospi- nutrition, or central venous catheters (Eggimann et al. talized patients in the USA (Hobson 2003; Pfaller et al. 2003, Krcmery & Barnes 2002). The increased incidence 1998b, Rangel-Frausto et al. 1999; Schaberg et al. 1991). of candidemia due to C. parapsilosis also is associated Some years ago Candida albicans accounted for with extended hospital stay, which leads to increased

Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 70–80% of the Candida isolates recovered from infected cost of medical care. Its spectrum of clinical manifes- patients (Banerjee et al. 1991; Beck-Sague & Jarvis tations include fungemia, endocarditis, peritonitis, 17 March 2009 1993; Fidel et al. 1999). However, infections due to arthritis, and endophthalmitis. This species displays non-albicans­ species have emerged over the past two many interesting ­biological features that are presumed 23 June 2009 decades, and a shift from C. albicans to species such as to be directly related to its virulence, such as its selec- Candida glabrata, Candida parapsilosis, and Candida tive adherence to prosthetic materials and formation of 02 July 2009 tropicalis has occurred (Fidel et al. 1999; San Miguel biofilms on plastic surfaces (Branchini et al. 1994; Pfaller et al. 2005). C. parapsilosis is now the second or third 1995), secrection of extracellular proteases (Fusek 1040-841X most common cause of candidiasis, behind C. albicans. et al. 1993, Merkerova et al. 2006, Pichova et al. 2001),

1549-7828 Address for Correspondence: Karl V. Clemons, Ph.D., Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose, CA 95128. Tel: (408) 998–4557, Fax: (408) 998–2723. E-mail:[email protected]

© 2009 Informa UK Ltd (Received 17 March 2009; revised 23 June 2009; accepted 02 July 2009) MCB ISSN 1040-841X print/ISSN 1549-7828 online © 2009 Informa UK Ltd 10.3109/10408410903213393 DOI: 10.3109/10408410903213393 http://www.informahealthcare.com/mby 421513 284 van Asbeck et al.

colonization of human hands (Bonassoli et al. 2005), of non-albicans species worldwide as a cause of BSI profileration in high concentration of glucose and lipids (Pfaller & Diekema 2002). The percentage of isolates of (Branchini et al. 1994), phenotypic switching (Laffey & non-albicans species varies considerably from region Butler 2005, Lott et al. 1993), and resistance to drugs and to region (Pfaller et al. 2006a; Pfaller et al. 2006b). In a inhibitors (Camougrand et al. 1986). Unfortunately, we previous study (Wingard 1995), spanning a period from have much to learn about the virulence of C. parapsi- 1952 to 1992, C. parapsilosis accounted for only 7% of losis and even more about the host defenses directed candidemia in cancer patients. Weems (1992) gave a against the organism. Therefore, studies increasing our summary of C. parapsilosis fungemia cases described ­knowledge about this pathogen are needed. before 1992. From 1962 to 1986, 11 different studies Since a previous review was written (Weems 1992), reported between 3% and 27% prevalence of C. parap- C. parapsilosis has only increased its standing as a silosis among Candida fungemia. Since 1990 C. parapsi- pathogen. It therefore is highly relevant to review the losis showed an increase in incidence and is the second recent literature on C. parapsilosis. While this article or third most common yeast species isolated from the was in preparation, last year an updated useful review blood in Asia and Latin American countries (Pfaller of many of the aspects of C. parapsilosis was presented et al. 2008a; Pfaller et al. 2000; Sandven 2000), and has (Trofa et al. 2008). We review the literature on C. parap- been commonly found in Europe as well (Pfaller et al. silosis; specific topics discussed include its epidemiol- 1999; Sandven 2000). Pfaller et al. (2002) reported the ogy, the molecular epidemiology, clinical perspectives, role of sentinel surveillance studies of candidemia and pathogenesis, and antimicrobial susceptibility and ­demonstrated differences among studies done between treatment. 1992 and 2001. The overall incidence in six different ­studies showed a prevalence between 7 and 21 percent of C. parapsilosis causing candidal BSI. They further Epidemiology showed that the distribution of C. parapsilosis caus- ing BSI in adults was 5–12% while the distribution in C. parapsilosis is a ubiquitous microorganism in the neonates was 24–45%. C. parapsilosis was most preva- natural environment. It is not only isolated easily from lent in patients less than 1 year of age. soil, seawater, and plants, but also can be isolated from Kao et al. (1999) conducted a prospective, active mucosal surfaces, skin and nails, where it belongs to the population-based surveillance for candidemia in two benign commensal flora of humans and mammals (De United States cities, Atlanta and San Francisco, during

For personal use only. Bernardis et al. 1999; Kuhn et al. 2004; Sanchez et al. 1993; 1992 to 1993. C. parapsilosis was the second most com- Weems 1992). The epidemiology ofC. parapsilosis in the mon Candida species, and was recovered from 21% of hospital environment is unique among Candida species, isolates from different patient populations. C. parapsi- because it is frequently isolated from physical surfaces. losis was recovered from 45% of the cases of candidemia It is a frequent cause of opportunistic infection, associ- in neonates. ated with high morbidity and mortality rates in hospi- The National Epidemiology of Mycosis Survey talized immuno-compromised patients (Girmenia et al. (NEMIS) performed an 18-month prospective study, 1996; Jarvis 1995). Although C. parapsilosis is an oppor- in surgical intensive care units (SICUs) and neonatal tunistic pathogen, the majority of patients who develop intensive care units (NICUs), from several centers in the disseminated candidiasis due to C. parapsilosis are not United States (Rangel-Frausto et al. 1999). C. ­parapsilosis immunosuppressed in the classical sense (Spellberg & was isolated from the blood in 7% of the cases in the Edwards 2002). Rather, the predominant risk factors for SICU, whereas a prevalence of 29% of C. parapsilosis was disseminated candidiasis due to C. parapsilosis, which identified in the NICU.

Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 are held in common among afflicted patients, are iatro- A 10-year study, from 1992 through 2001, recorded genic and/or nosocomial factors (Spellberg et al. 2006). the distribution of BSI isolates of different Candida ­ This species has been particularly associated with BSI species (Pfaller & Diekema 2004). Isolates were collected in very low birth weight neonates (Campbell et al. 2000; from 250 medical centers in 32 nations worldwide. da Silva et al. 2001; Damjanovic et al. 1993; Huang et al. C. parapsilosis accounted for 13% and was the third most 1998; Huang et al. 1999; Sarvikivi et al. 2005; Saxen et al. common Candida species isolated from BSI. 1995; Solomon et al. 1986; Welbel et al. 1996), but is also Pfaller et al. (1998a) previously reported C. parapsilo- seen frequently in patients with catheter-associated sis had a higher prevalence in Europe, Canada and Latin candidemia and/or with intravenous hyperalimentation America compared to the United States. In 1997 and (Cano et al. 2005; Huang et al. 2004; Levin et al. 1998; 1998 the SENTRY Antimicrobial Surveillance Program Levy et al. 1998; Marais et al. 2004). reported 12 months of BSI surveillance in the United Although C. albicans continues to predominate, States, Canada and Latin America (Diekema et al. several surveillance programs report the emergence 1999; Pfaller et al. 2000). Of 634 BSI, 8.4% was due to C. Candida parapsilosis: a review 285

parapsilosis. There was a difference of frequency of BSI of C. parapsilosis (Pfaller et al. 2005c). C. parapsilosis due to C. parapsilosis between countries and difference and C. tropicalis were predominant in the Asia-Pacific in years. There was a decline in frequency of C. parap- and Latin American regions but was less so in Europe, silosis fungemia in both Canada and Latin America Canada and the United States. between 1997 (23%; 38% respectively) and 1998 (7%; In the surveillance study performed by the European 19%). An increase in BSI due to C. parapsilosis in the Confederation of Medical Mycology (ECMM), spe- United States was noted from 9% in 1997 to 15% in 1998 cies distribution of Candida bloodstream infections (Diekema et al. 1999; Pfaller et al. 2000). The SENTRY of 2089 cases were documented by 106 institutions in Antimicrobial Surveillance Program studied candi- seven European countries from Sept 1997–Dec 1999 demia in 20 European medical centers (13 nations) in (Tortorano et al. 2006, Tortorano et al. 2004). In a range 1997 (Pfaller et al. 1999). C. parapsilosis was, with 21%, of patient populations, C. parapsilosis accounted for the second most common Candida species causing BSI 13% of the cases of candidemia, with a range of 6–30%, in Europe. The greatest prevalence ofC. parapsilosis was being the third most common Candida species after noted in the Latin American hospitals. Over a 3-year C. albicans (56%) and C. glabrata (14%) (Tortorano et al. period, from 1995 to 1998, Edmond et al. (1999) reported 2004). Variation in prevalence was noted and has been C. parapsilosis (21%) as the third most common Candida attributed to the different patient populations hospi- species causing nosocomial BSI, in data obtained from talized in the different units (Tortorano et al. 2004). In 49 hospitals across the United States (1999). addition, there was variation between countries noted A decreasing trend in the rate (overall decrease, 10 to (Tortorano et al. 2006). C. parapsilosis was identified in 11%) of C. albicans isolation was noted over a 6.5 years 15% in cancer patients (Tortorano et al. 2004). This study period (1997–2003) from the ARTEMIS DISK Global reported C. parapsilosis the most frequent Candida Antifungal Surveillance Study including 121 different species identified in premature neonates (29%). In institutions (Pfaller et al. 2005c). In contrast, C. parap- another study, the ECMM performed an epidemio- silosis showed an increase of 3% frequency of isolation logical prospective survey of candidemia in one Italian over this time period. From 1997 to 1998, C. parapsilo- region, Lombardy, for a 28-month period (September sis accounted for 4%, and in 2003 for 7% (Pfaller et al. 1997–December 1999) (Tortorano et al. 2002). Fifteen 2005c). percent of the cases of candidemia were caused by Diekema et al. ( 2002) performed prospective surveil- C. parapsilosis, and it was the second most common lance for candidemia at 16 hospitals in the State of Iowa cause of candidemia, behind C. albicans (59%). C. parap-

For personal use only. between 1998 to 2001. C. parapsilosis was ­identified in silosis was isolated with the highest frequency in prema- 7%, the fourth most common Candida species. However, ture neonates and hematological patients, comprising the percentage of candidemia caused by C. parapsilosis 44 and 24% of isolates. Another study from the ECMM, trended higher among infants less than 1 year of age in the same time period from several hospitals widely (17%) compared to other age groups (6%) (Diekema distributed throughout Spain, showed a prevalence of et al. 2002). 22% of C. parapsilosis isolates from adults (Peman et al. Between 2001 and 2004 the distribution of Candida 2005). In pediatric patients C. parapsilosis was the most species of clinical isolates (blood or sterile-site) were prevalent species (50%). tested among 91 medical centers worldwide (Asia- The advent of new medical therapies and proce- Pacific, Europe, Latin America, and North America) dures to treat cancer, such as steroids, the increase in and C. parapsilosis accounted for 14% (Pfaller et al. surgical procedures, widespread use of broad spectrum 2006b). In another report, during the 2001–2002 study antibiotics and prolonged hospital stay are all linked period, a prevalence of 14% was found for C. parapsi- to the increase of Candida bloodstream infections

Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 losis isolates obtained from 54 different centers world- (Eggimann et al. 2003; Sofair et al. 2006). The shift in the wide (Pfaller et al. 2005b). Nucci et al. (2001) reported epidemiology towards C. parapsilosis infections may a study of C. parapsilosis and C. albicans candidemia in be especially linked to the increase, which occurred a tertiary hospital in Brazil. Patients with a candidemia in the past two decades, in incidence of blood stream of C. parapsilosis were less ill, more had cancer in com- infections associated with intravascular devices (San plete remission, fewer had antibiotics, were less likely Miguel et al. 2005). The majority of the C. parapsilosis to be hypotensive and showed a lower mortality com- infections are due to exogenous acquisition. An impor- pared to patients with a candidemia caused by C. albi- tant study that recognized this showed that a series of 13 cans (Nucci et al. 2001). patients with C. parapsilosis fungemia did not have the In 2004 and 2005 the Global Surveillance study organism isolated from other sites before the fungemia reported species distribution of Candida species (clini- (Meunier-Carpentier et al. 1981). This is in contrast with cal isolates from blood or sterile site) among 60 medi- fungemia due to other Candida species. Further to this cal centers worldwide, and reported a 14% prevalence point, there is a significantly increased risk of systemic 286 van Asbeck et al.

disease ­associated with intravascular catheters, pros- and glucose-containing solutions (Clark et al. 2004; thetic devices and parenteral nutrition (Levin et al. 1998; Deresinski et al. 1995; Levy et al. 1998; Posteraro et al. Tortorano et al. 2006; Zancope-Oliveira et al. 2000). 2004; Solomon et al. 1986; Solomon et al. 1984; Weems C. parapsilosis has the ability to produce an extracellular et al. 1987). polysaccharide or slime, and this property is believed to With the use of azoles there has been an aid adherence and biofilm formation on plastic devices ­epidemiological shift of hematogenous candidiasis to (Levin et al. 1998; Ramage et al. 2005). The source of the those caused by non-albicans Candida species, espe- infection by this yeast species is not always apparent. cially C. krusei and C. glabrata (Abi-Said et al. 1997; Kao In many neonatal intensive care units (NICU), et al. 1999). The rise of C. parapsilosis correlates with C. parapsilosis has emerged as the predominant increased use of caspofungin and voriconazole (Forrest pathogen causing invasive infection, and significantly 2008). Girmenia et al. (1996) showed an overall decrease increases the morbidity and mortality of severely ill of isolation of C. albicans with a concomitant increase infants who require care in a NICU (Kao et al. 1999; in isolation of C. parapsilosis among adult patients with Krcmery et al. 1999; Kuhn et al. 2004; Levy et al. 1998; cancer. This indicates that even among older patients Roilides et al. 2004; Saiman et al. 2001; Stamos & Rowley the incidence of C. parapsilosis may be on the rise. The 1995). The proportion of infections due to C. parapsi- crude mortality rate associated with C. parapsilosis losis has increased among neonates. C. parapsilosis infection has been estimated to be 30%, lower than that comprised less than 10% of isolates in the 1980s and reported for invasive infection with C. albicans (79%) early 1990s (Baley & Silverman 1988; Faix 1984; Huttova or other non-albicans Candida spp. (mean 78%) (Horn et al. 1998a). More recently, studies reported propor- et al. 1985; Nucci et al. 2001; Pappas et al. 2003). tions of 50–60% of C. parapsilosis infections among neonates (Benjamin et al. 2000; Kossoff et al. 1998; Levy Molecular epidemiology et al. 1998; Rodriguez et al. 2006). The proportion of infections due to C. parapsilosis has increased among Biochemical methods have traditionally been relied neonates. As neonates mature, the incidence of C. par- on to identify C. parapsilosis in the clinical microbiol- apsilosis decreases (Pfaller & Diekema 2002; Tortorano ogy laboratory, although occasionally these can lead to et al. 2006). Changes in neonatal intensive care practices misidentification (Fenn et al. 1994; Heelan et al. 1998; may be related to the emergence of C. parapsilosis as Pfaller et al. 2008a; Ramani et al. 1998; Wadlin et al. an important pathogen in very low birthweight infants 1999). Due to problems in the traditional classification

For personal use only. (Clerihew et al. 2007). Cases can persist in units for of yeast within the genus Candida, molecular tech- years (Sarvikivi et al. 2005) and the case fatality rate can niques are needed to classify and identify medically be high (83%) (Saxen et al. 1995). Cross-transmission important yeast species. This will help us to under- between patients, especially among neonates, through stand the evolutionary relationships between these the hands of healthcare workers plays an important organisms. The application of molecular procedures role in the spread of C. parapsilosis, contributing to the has already resulted in major reclassification of many high isolation rate of C. parapsilosis. C. parapsilosis is species. Comparative studies with chromosomal DNA a frequent fungal colonizer of the subungual space of have been very helpful to differentiate Candida species healthy volunteers (Abi-Said et al. 1997; McGinley et al. from each other and also to delineate different strains 1988; Weems 1992). Several reported outbreaks have within species. The ideal method for differentiating been caused via direct interaction between healthcare C. parapsilosis at a subspecies level should be able to workers and the newborn, through the placement discriminate between strains that are epidemiologi- or manipulation of catheters, the site through which cally unrelated, should be highly reproducible both C. parapsilosis entered the bloodstream, as well as liquid intra- and inter-laboratory, should take minimal time, Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 glycerin suppositories and topical ointments (Barchiesi should be capable of processing a large number of et al. 2004; Campbell et al. 2000; Huang et al. 1999; Kuhn strains, should require a minimum of specialized et al. 2004; van Asbeck et al. 2007; Welbel et al. 1996). equipment, and be relatively inexpensive (McCullough Hypoxemia, bradycardia, respiratory distress requiring et al. 1996). It is unclear whether the emergence of incubation and dissemination to secondary sites are pathogenic isolates of C. parapsilosis in varying clini- less common with C. parapsilosis fungemia in new- cal institutions is due to the genetic diversity and the borns, compared to C. albicans fungemia (Huang et al. virulence of some strains, or to widespread favorable 2000). environmental conditions persisting in compromised Other outbreaks have been reported, such as out- hosts (Dassanayake & Samaranayake 2000). Detailing breaks of C. parapsilosis caused by contamination of the genotypic characteristics are not only important for hyperalimentation solutions, intravascular pressure a more appropriate taxonomy, it could also greatly con- monitoring devices, ophthalmic irrigating solutions tribute to our understanding of the epidemiology and Candida parapsilosis: a review 287

the pathogenic mechanisms of this emerging pathogen in strains from ITS groups I and III, a polymorphism (Weems 1992). Hospital outbreaks have been associ- within group II was observed (van Asbeck et al. 2008a). ated with specific strains of C. parapsilosis by use of the Roy and Meyer (1998) studied the DNA relatedness various methods we will discuss (Shin et al. 2001; and RFLP patterns of whole-cell DNA and the general Barchiesi et al. 2004; Clark et al. 2004; Garcia San Miguel properties of 14 C. parapsilosis isolates and observed et al. 2004; Marais et al. 2004). Molecular typing also has unrelatedness of the three previously described groups the utility of discerning “pseudo-outbreaks,” contami- at the species level. The low degree of the DNA relat- nated processing materials leading to false conclusion of edness, less than 25% DNA identity, among the three a case cluster (Deresinski et al. 1995; Schar et al. 1990). ­different DNA groups of C. parapsilosis suggested Genetic analysis of C. parapsilosis has been hin- that they represent distinct species. Various studies dered by the lack of characterized sexual cycle (Logue ­supported this idea of possible separation of C. parap- et al. 2005), ploidy (aneuploid and/or diploid) of the silosis isolates (Cassone et al. 1995; De Bernardis et al. organism (Fundyga et al. 2004) and the unavailability 1999; Kurtzman & Robnett 1998; Lin et al. 1995; Pontieri of appropriate molecular genetic tools (Nosek et al. et al. 2001). The internally transcribed spacer (ITS) 2002a). Various DNA typing method studies report that regions flanking the 5.8S rDNA in yeasts have greater C. parapsilosis can be divided into three groups based heterogeneity than the 5.8S region itself. Using this on isoenzyme analysis, internally transcribed spacer observation, for example, Lin et al. (1995) concluded (ITS) sequences of DNA within the ribosomal cassette, there were 3 different genotypes in C. parapsilosis RAPD profiles, RFLP typing, electrophoretic karyotype based on sequence analysis. patterns, multilocus enzyme electrophoresis, morpho- Based on their ITS (mostly ITS1) region sequences, typing, multilocus sequence typing (MLST), and DNA Tavanti et al. (2005) proposed to recognize Candida relatedness (Lehmann et al. 1992; Lin et al. 1995; Lott orthopsilosis and Candida metapsilosis as species sepa- et al. 1993; Roy & Meyer 1998; Scherer & Stevens 1987; rate from C. parapsilosis. Thus far, these sibling species Tavanti et al. 2005). Although division into three groups are phenotypically indistinguishable from C. parap- can be achieved, when subtyping within the three silosis sensu stricto. DNA sequence analysis showed groups is performed, it was noted that a large number of conformity of C. parapsilosis with previous group I, the isolates are indistinguishable. C. orthopsilosis with group II and C. metapsilosis with Scherer and Stevens (1987) described a useful group III (Lin et al. 1995; Roy & Meyer 1998; Tavanti method for the extraction of DNA from the yeast of et al. 2005). Based on sequence analysis of four gene

For personal use only. Candida spp., followed by digestion and restriction fragments, nine C. orthopsilosis isolates showed nucle- endonucleases and electrophoresis of DNA fragments. otide sequence diversity. This suggests great hetero- Seven C. parapsilosis isolates typed in this manner geneity among the C. orthopsilosis isolates, compared could be placed in 3 major DNA groups with, initially, to the mainly clonal C. parapsilosis. Lack of diversity 5 subtypes. As more isolates were studied, greater among group I isolates had been suggested by karyo- genotypic diversity became apparent, for example, typing (Carruba et al. 1991; Lott et al. 1993; Shin et al. Deresinski et al. (1995) found a unique RFLP sub- 2001). The sequence homogeneity in group I isolates type, VII-3, identified in a common source outbreak, suggests they emerged more recently than the other and a recent study done by van Asbeck et al. (2008a) types. Some hospital outbreaks have been related spe- examined the molecular epidemiology of the global cifically to group II (Lin et al. 1995; Zancope-Oliveira and temporal diversity of C. parapsilosis. In this study et al. 2000), although most would appear to be related 15 new subtypes were observed, with one dominant to group I. subtype, VII-1 (82% of 536 C. parapsilosis isolates). Our laboratory compared two predominant typing Dividing the isolates into VII-1 versus non-VII-1 methods, RFLP and MLST, and reported C. parapsilosis Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 showed temporal variation for the USA pre-1995 ver- sensus stricto appear to be nearly identical to the pre- sus post-1995 (p < 0.0001) and versus Europe pre-1995 dominant RFLP subtype VII-1, and cannot be subtyped (p < 0.0001). Genotype distribution differed among by RFLP and MLST (van Asbeck et al. in press). However, localities (p < 0.0001); Mexico was unique (p < 0.05) due C. orthopsilosis can be subtyped by both MLST and RFLP to the high proportion of non-VII-1. The prevalence of (van Asbeck et al. in press). C. parapsilosis RFLP type VII-1 apparently has risen in Tavanti et al. (2007) used amplification fragment the USA and current isolates show some variation in dis- length polymorphism (AFLP) to identify C. orthopsilosis tribution of types in some non-USA locales compared at the species level and efficiently delineate intraspe- to the USA. There were no differences in distribution of cific genetic relatedness because of the high percentage types comparing babies versus adults, or blood stream of polymorphic bands resulting from the AFLP. Clonal isolates versus colonizing or environmental isolates. In reproduction and recombination both contribute to contrast to the conserved restriction fragment profiles C. orthopsilosis genetic population structure. This 288 van Asbeck et al.

study also reported the clinical relevance of C. orthop- compact and encode the same set of genes arranged in silosis. Screening a large collection of C. parapsilosis, an identical order. However the size of C. orthopsilosis 5% of the infections/colonizations were identified as and C. metapsilosis mtDNA represents about two- C. orthopsilosis. thirds that of the C. parapsilosis sensus stricto. Earlier, Recently, Gomez-Lopez et al. (2008) describe the Rycovska et al. (2004) assessed the polymorphism at the prevalence of the two newly described species C. metap- level of mtDNA and indicated that group II isolates all silosis and C. orthopsilosis (described below (Tavanti have a circular mtDNA, whereas the mtDNA in group et al. 2005)) causing bloodstream infections in Spain. The I and III is mostly linear. Kosa et al. (2006) showed prevalence of these species appeared to be important, C. orthospilosis and C. metapsilosis differ in the molecu- representing the fifth and sixth most ­common species lar form of the mitochondrial genome, circular—versus (1.7% and 1.4% for C. metapsilosis and C. orthopsilosis linear—mapping, whereas C. parapsilosis sensus stricto respectively) (Gomez-Lopez et al. 2008). This study also possesses a linear mitochondrial genome. provided evidence that these species may behave as Mitochondrial telomeres are unique among human pathogens. A more recent paper also studied C. ­parapsilosis compared to related species (Nosek geographical distribution of the sister species (Lockhart et al. 2002b). Thus, mtDNA enables us to discriminate et al. 2008a). C. orthopsilosis comprised 6.1% and C. between the groups of C. parapsilosis and it represents a metapsilosis 1.8% of 1,929 isolates. C. orthopsilosis was powerful tool to distinguish species. most common in South America. Somewhat in con- Similarly, Iida et al. (2005) found that most of the trast to our observations (van Asbeck et al. 2008a), C. parapsilosis strains from Japan and Brazil tested for C. orthopsilosis appeared to have increased in recent ITS sequences belonged to one of the three genetically years. Mexico had a high frequency of C. orthopsilosis, distinct groups (I, II, and III). However, they found that likely a reflection of the same trends as our increase of 5 strains showed differences in ITS sequence from those non-VII-1 types in that country (van Asbeck et al. 2008a). already reported, and based on this, suggested the pres- Lockhart et al. (2008b) reported that an apparently ence of a new major DNA group (IV) among the genetic closely related species, Lodderomyces elongisporus, groups within the C. parapsilosis family. is mislabelled by routine clinical laboratory methods Dominance of these C. parapsilosis group I isolates, as C. parapsilosis. Once erroneously considered to be and its geographic spread, might be due to the clonal the teleomorph of C. parapsilosis (van der Walt 1966), mode of reproduction, shown by the low nucleotide L. elongisporus can be distinguished phenotypically variability observed within the species (Fundyga et al.

For personal use only. from C. parapsilosis as they produce different colored 2004; Tavanti et al. 2005; Tavanti et al. 2007). colonies on ChromAgar medium. On cornmeal agar, A new DNA probe, Cp3-13 for DNA fingerprinting, L. elongisporus forms short pseudohyphae indistin- has been described, which not only discriminated dif- guishable from C. parapsilosis. On sporulation medium, ferences between strains, but also identified changes only L. elongisporus forms ascospores. The species dif- in a clonal population after a few hundred genera- ferentiation is supported by DNA/DNA homology and tions in vitro or changes that have occurred in vivo in sequencing of large-subunit rRNA genes. In their large infected persons (Clark et al. 2004; Enger et al. 2001; population studied (Lockhart et al. 2008b), L. elongis- Sofair et al. 2006). Recently, a microsatellite method, porus could be differentiated as 10/542 isolates from a with high discrimination and reproducibility, has collection ostensibly all C. parapsilosis; all of the former been reported that further differentiates group I were blood stream isolates. C. parapsilosis isolates with high discriminatory Camougrand et al. (1988) used restriction analysis of power (Lasker et al. 2006). Microsatellites are short mitochondrial DNA of C. parapsilosis reference strains 2- to 10 bp multiple tandem repeats, and have a high and showed great differences between them. By probing mutation rate. This method makes it possible to detect Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 the restriction patterns with S. cerevisiae mitochondrial microevolutionary variations of isolates obtained DNA fragments, further differentiation could be made. from different body sites, and may facilitate detection Nosek et al. (2004) determined the complete mitochon- of outbreaks. drial DNA (mtDNA) sequence of C. parapsilosis, repre- Kosa et al. (2007) constructed a collection of replica- sented by linear DNA molecules terminating with arrays tive shuttle vectors, a system for genetic transformation of tandem repeats of a 738 bp unit, varied in number of the yeast C. parapsilosis. These vectors, which allow and size, termed mitochondrial telomeres. Recently, expression of the cloned genes, intracellular localization Kosa et al. (2006) studied the complete sequence of of protein products or monitoring of a promotor activity, mitochondrial DNA of the sibling species and observed may contribute to the investigation of diverse biological C. metapsilosis likely diverged from a common ancestor features related to C. parapsilosis (2007). prior to the split of C. orthopsilosis and C. parapsilosis A sequencing project of C. parapsilosis nuclear sensu stricto. All three sibling species genomes are highly genome would be important for better understanding Candida parapsilosis: a review 289

the biology of this pathogenic yeast species at the onychomycosis in Malta (Vella Zahra et al. 2003). One molecular level. Understanding the genetic diversity of case of onychomycosis caused by C. parapsilosis, involv- the yeast requires further study and may lead to insight ing both the toenail and the fingernail, in a 35-day-old in the pathogenesis of fungal infections, and ultimately patient has been reported (Koklu et al., 2007). With all may make it possible to define proper preventive meas- positive cultures from nails, supporting histopathologi- ures (Roy & Meyer 1998). cal evidence of infection is needed to distinguish infec- tion from colonization. Folliculitis due to C. parapsilosis has been described by Li et al. (1988). Clinical aspects C. parapsilosis has been associated with disease of the external or middle ear (Dorko et al. 2004; Garcia-Martos C. parapsilosis is an important opportunistic pathogen et al. 1993; Vennewald et al. 2003). The risks appear to that causes infections ranging from thrush to invasive be ocean swimming, trauma and prior antibacterial disease such as fungemia, endocarditis, endophthalmi- therapy. tis, arthritis, and peritonitis, all of which usually occur in association with invasive procedures or prosthetic Mucosal devices. We will describe only the most frequent infec- tions caused by C. parapsilosis. The primary mucosal infection due to C. parapsilosis is vaginal. In the majority of women with Candidal vaginitis it is due to C. albicans, which causes 80% to Superficial Infections 92% of all cases of Candida vaginitis worldwide (Singh Frequent isolation of C. parapsilosis from pathological et al. 1972; Trama et al. 2005). In immunodeficient lesions of nails and skin, with a distal subungual type women, vaginal colonization by non-albicans species of onychomycosis often occurs with this organism (De is more frequent (Trama et al. 2005). Weems (1992) Bernardis et al. 1999; Figueiredo et al. 2007; Mujica et al. concluded that vaginitis caused by C. parapsilosis 2004; Pfaller et al. 1995; Segal et al. 2000; Strausbaugh is infrequent. However, an increase in frequency of et al. 1994). Risk factors significantly associated with vaginitis caused by C. parapsilosis has been observed ­colonization in patients are prolonged antibiotic among healthy women (Nyirjesy et al. 2005; Trama therapy, parenteral nutrition, duration of stay in the et al. 2005). C. parapsilosis can be responsible for ­hospital, ­surgery, indwelling devices, diabetes, obes- vulvovaginal symptoms, such as itching, burning, dys-

For personal use only. ity, malignancy, elderly, and neonates of very low birth pareunia and vaginal discharge, but can also appear weight (Bendel 2003; Dorko et al. 2005; Figueiredo et al. asymptomatically (Nyirjesy et al. 2005). The change 2007; Jautova et al. 2001). of species distribution, non-albicans species such as C. parapsilosis is second to C. albicans as the most C. glabrata, C. parapsilosis, and C. tropicalis becom- common Candida causing onychomycosis (Brilhante ing more frequent, can be related to factors that might et al. 2005; Dorko et al. 2002a; Khosravi & Mansouri change the vaginal environment and flora (Trama et al. 2001). However, some studies observed an even higher 2005). These factors could be increasing use of azole prevalence of onychomycosis caused by C. parapsi- drugs, an aging population, increased exogenous use losis. Segal et al. (2000) reported a high prevalence of of hormones to manage menopause, and/or more C. parapsilosis among onychomycosis patients obtained medical and hospital contact in the patients sampled from two different centers in Israel. C. parapsilosis was (Trama et al. 2005). Cassone et al. (1995) showed that the predominant Candida species, recovered from both ~10% of vaginal candidiasis is caused by C. parapsilo- fingernail and toenail infections (Segal et al. 2000). sis. Nyirjesy et al. (2005) reported 9% of vaginitis cases Figueiredo et al. (2007) reported 41% of the 200 samples were caused by C. parapsilosis. C. parapsilosis, like Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 recovered from fingernails of Candida species were C. albicans, produces acid proteinases, enzymes which C. parapsilosis, which is in agreement with Rodrigues- are associated with vaginopathic potential (Agatensi Soto et al. (1993), who identified C. parapsilosis as et al. 1991; Nyirjesy et al. 2005). Secretion of aspartyl the prevalent species in onychomycosis involving the proteinases is elevated in vaginitis caused by these fingernails. In addition, Oliveira et al. (2006) reported vaginopathic strains. Women suffering multiple epi- C. parapsilosis as the Candida species most frequently sodes of vulvovaginitis, and with theoretically compro- isolated from onychomycosis lesions. Recently, in a mised integrity of the vaginal mucosa, may be more study among Algerian military personnel, C. parapsilosis susceptible to infection with C. parapsilosis because of was the predominant yeast species causing both super- the acid proteinase activity of the organism (Nyirjesy ficial fungal infection and onychomycosis of the foot et al. 2005). Vaginitis caused by this pathogen seems (Djeridane et al. 2006; Djeridane et al. 2007). In addi- to respond to a variety of antifungals (Nyirjesy et al. tion, C. parapsilosis was the most common yeast causing 2005). 290 van Asbeck et al.

Urinary tract infections two decades fungal endocarditis has increased in inci- dence, carrying with it a high risk of mortality (Garzoni Primary urinary tract infections due to C. parapsilosis et al. 2007; Lopez-Ciudad et al. 2006); this is one of the have markedly increased in recent years and are associ- most serious manifestations of candidiasis. A long dura- ated with the presence of urinary catheters (Camacho tion of illness has been reported in patients suffering et al. 2007; Passos et al. 2005; Tamura et al. 2003). The non-albicans endocarditis, so prolonged treatment is adherence of microorganisms to the surface is a deter- required to avoid grave consequences (Khan et al. 2007). mining factor in colonization and infection (Tamura Among yeast-related endocarditis, C. parapsilosis is the et al. 2003). Recently, in a study of Camacho et al. (2007), most important non-albicans species isolated (Garzoni antimicrobial activity of chlorohexidine and gentian et al. 2007; Khan et al. 2007). violet reduced the adherence of C. parapsilosis. Clusters of cases involving prosthetic valves have been reported (Diekema et al. 1997). Garzoni et al. Systemic (2007) described intraoperative contamination (e.g. cardiac bypass equipment, tears in surgical gloves) to In contrast to C. albicans infections, C. parapsilosis be the most common source of infection in outbreaks of ­infections may occur without prior colonization, espe- C. parapsilosis infective endocarditis (Diekema et al. cially in young children (Shin et al. 2001). C. parapsi- 1997; Johnston et al. 1994). The most prevalent pre- losis causes 17–50% of fungemia in children (Abi-Said disposing factors for fungal endocarditis caused by et al. 1997; Krcmery & Barnes 2002; Krcmery et al. 1999; C. parapsilosis are prosthetic valves, then, in this order, Viscoli et al. 1999; Wingard 1995). The clinical pic- ­intravenous drug use, parenteral nutrition, antibiotic ture of fungemia may include shock and renal failure therapy, preexisting valvular heart disease, prior epi- (Almirante et al. 2006). Direct access to the bloodstream sode of endocarditis and reconstructive cardiovascular via indwelling devices might be an explanation of the surgery (Brandstetter & Brause 1980; Garzoni et al. 2007; cause of infections without prior colonization at other Khan et al. 2007; Rubinstein et al. 1975; San Miguel et al. sites (Levin et al. 1998; Traore et al. 2002; Weems 1992). 2006; Tonomo et al. 2004; Weems 1992). Abdominal sur- Unlike other Candida species, catheter-related fungemia gery and immunosuppression have also been described caused by C. parapsilosis has a higher rate of spontane- as risk factors. The aortic valve is the first, and mitral valve ous clearance and a much lower rate of establishment at the second, most commonly involved valve in infection secondary sites (Levy et al. 1998; Weems 1992). of native valves (Garzoni et al. 2007; Weems 1992), with

For personal use only. Breakthrough fungemias during antifungal treat- intravenous drug use the most common predisposing ment appear especially common in cancer patients and factor (Garzoni et al. 2007). The overall mortality of these are associated with an infected foreign body, such as patients was high (42%). Among those treated with con- catheters, and insufficient antifungal treatment (Safdar ventional antifungals and adjunctive surgery, mortality et al. 2002). Krcmery et al. (1999) reported breakthrough was lower (Johnston et al. 1994). Peripheral embolic and fungemia among neonates during fluconazole therapy hemorrhagic events are the most common complica- and prophylaxis. The presentation of C. parapsilosis tions (44%) of C. parapsilosis endocarditis (Garzoni et al. fungemia in neonates can be subtle including thrombo- 2007). cytopenia and leucopenia (Huang et al. 1999). C. parap- silosis fungemia has a lower mortality than bloodstream infections due to other Candida species. Peritonitis Fungal peritonitis is an uncommon but potentially life- threatening complication of continuous ambulatory Endocarditis peritoneal dialysis (CAPD) (Amici et al. 1994; Bren 1998; Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 As a cause of endocarditis, C. parapsilosis has demon- Chen et al. 2004; Chen et al. 2006; Johnson et al. 1985; strated a tendency to persist, even despite suppressive Kaitwatcharachai 2002). C. parapsilosis has become the therapy, and recrudesce if suppression is discontinued. most prevalent pathogen of fungal peritonitis (Chen This can be misleading, in that patients with C. parap- et al. 2006). This organism, which is a common skin and silosis endocarditis are reported in the literature while subungual colonizer, has the ability, in high glucose still receiving suppressive therapy (and sometimes with concentrations, to adhere easily to prosthetic material short follow-up post-surgery, and without attempts to by extensive biofilm formation on the surface of the evaluate fungemia), resulting in a false impression of plastic catheter. The high glucose content of dialysate, cure (Galgiani & Stevens 1977). Serologic follow-up dur- and catheter implantation in peritoneal dialysis patients ing and after therapy may be useful (Galgiani & Stevens causes this high prevalence of fungal peritonitis caused 1977). Weems (1992) described some patients with endo- by C. parapsilosis (Chen et al. 2006). The mechanism ofC. carditis caused by C. parapsilosis before 1992. In the past parapsilosis infections is considered to be transmission Candida parapsilosis: a review 291

by skin colonization of C. parapsilosis via the catheter albicans the most frequent subspecies (30%). C. parap- lumen (Kaitwatcharachai 2002). silosis accounted for 21% of all Candida endophthalmi- An earlier study of Manzano- Gayosso et al. (2003) tis infections. reported C. albicans and C. parapsilosis as the most com- A few cases of keratitis have been reported, with risk mon species among 165 patients with peritonitis receiv- factors such as corticosteroid use, corneal transplanta- ing CAPD treatment. Other studies showed C. parapsi- tion and laser in situ keratomileusis (LASIK) (Bourcier losis the most prevalent pathogen of fungal peritonitis in et al. 2003; Muallem et al. 2003; Solomon et al. 2004). patients receiving peritoneal dialysis (Chen et al. 2006; Since treatment, such as surgery and antifungal therapy, Wong et al. 2000). Recently, Chen et al. (2006) reported can save vision, evidence of intraocular infection should a percentage of 86% (19 cases), of fungal peritonitis be recognized as early as possible (Feman et al. 2002). caused by Candida species, of these, 41% (9 cases) were C. parapsilosis. Fifty percent of these patients developed Joint diseases severe complications, with abscess formation and per- sistent peritonitis after catheter removal (Chen et al. Candida arthritis is most commonly seen among intra- 2006). venous drug users (Vasquez et al. 2002). Nosocomial Wang et al. (2000) showed that the presence of C. parapsilosis arthritis has been reported in only a few abdominal pain, antibiotic use within 3 months before cases, involving the knee, shoulder and wrist (De Clerck fungal peritonitis, bowel obstruction and a catheter kept et al. 1988; Diekema et al. 1997; Legout et al. 2006; in situ seems to be associated with the development of Salo et al. 1990; Smith et al. 1987; Vasquez et al. 2002; fungal peritonitis and necessitate CAPD discontinuation Yarchoan et al. 1979) Arthritis caused by C. parapsilo- (removal of the catheter) (Kaitwatcharachai 2002; Wong sis is associated with joint prostheses, probably due to et al. 2000). Kaitwatcharachi (2002) showed that either the increased ability of this micro-organism to adhere abdominal pain or antibiotic use in the previous three to plastic (Brooks & Pupparo 1998; Cushing & Fulgenzi months were risk factors for fungal peritonitis prior to 1997; Hennessy 1996; Wada et al. 1998). Arthritis, pro- CAPD discontinuation. Prior gram negative bacterial duced by C. parapsilosis, can result through direct inoc- peritonitis is also a risk factor for development of fun- ulation of the fungus at arthrocentesis and is sporadic gal peritonitis (Kaitwatcharachai 2002). Whereas there in older individuals (Cuende et al. 1993). Risk factors is no consensus whether or when peritoneal catheters for these sporadic incidents include diabetes mellitus, should be removed, rapid catheter removal has been intravenous drug use, and immunosuppression (Cuende

For personal use only. recommended in C. parapsilosis peritonitis in CAPD et al. 1993). patients (Bren 1998; Kaitwatcharachai 2002). Chen et al. (2006) showed that patients with C. parapsilosis perito- Pancreatitis nitis developed more complications and have a worse prognosis than those infected with other Candida spe- There are a growing number of reports of pancreatic cies in peritoneal dialysis-associated fungal peritonitis. infections due to Candida species, most commonly Because of different severity and prognosis, C. parapsi- C. albicans, mainly with previous abdominal manipula- losis peritonitis in peritoneal dialysis patients should be tion, such as previous pancreatic drainage procedures treated more aggressively than other Candida species (percutaneous or surgical) (Robbins et al. 1996). Fungal (Chen et al. 2006). pancreatitis due to non-albicans species has increased in incidence and is attributed to several factors, such as the use of broad-spectrum antibiotics, parenteral Endophthalmitis nutrition as well as the increase in use of immunosup- C. parapsilosis has been known as a cause of epidemic pressive agents (Robbins et al. 1996). Only a few cases of Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 of post-cataract endopthalmitis caused by intrinsi- pancreatic infections (infected pancreatic necrosis and cally ­contaminated, intraocular lens-irrigating solu- pancreatic abscesses) due to C. parapsilosis have been tion (McCray et al. 1986; O’Day 1985; O’Day et al. 1987; described (Ibanez & Serrano-Heranz 1999; Kull et al. Stern et al. 1985). In one study 4% of patients exposed 1999; Gautret et al. 1998). to the contaminated solution developed C. parapsilosis ­endopthalmitis (McCray et al. 1986). Although other Meningitis sporadic postoperative intraocular infections with C. parapsilosis have been reported, hematogenous Up to 1992, in the review article by Weems (1992) one endophthalmitis appears to be rare (Feman et al. 2002; case of meningitis caused by C. parapsilosis was reported Weems 1992). Recently, Marangon et al. (2004) reported (Faix 1983). Several cases of meningitis caused by this Candida species as the most common cause of endog- organism have since been described, especially among enous endophthalmitis in their institution, with C. neonates (Dorko et al. 2002b; Huttova et al. 1998b). 292 van Asbeck et al.

Surgery, antibiotic treatment, parenteral nutrition, ­colonization and subsequent infection of host tissues skin folliculitis, fungemia and the use of intravascular by a ­potentially pathogenic Candida spp. C. parapsi- and intraventricular catheters are potential risk factors losis, which is thought to be acquired from exogenous (Huttova et al. 1998b; Jimenez-Mejias et al. 1993; Weems sources, adheres to indwelling devices, and after adher- 1992). ence invades the host (Kuhn et al. 2004). C. albicans and other non-albicans Candida species adhere to a greater extent to mucosal tissue than does C. parapsilosis (Klotz Pathogenesis et al. 1983, Wingard 1995). A decreased adherence to epithelial cells by C. parapsilosis compared to C. albi- Although very little on this subject has been studied, cans and C. tropicalis has been observed (Krcmery & in this section we will discuss what is currently known Barnes 2002, Weems 1992) and the reduced pathogenic about virulence factors of C. parapsilosis and host potential of C. parapsilosis related to its adhesive prop- defense against this organism. erties (Branchini et al. 1994). However, Panagoda et al. (2001) observed adhesion by C. parapsilosis skin iso- lates to human buccal epithelial cells was higher than Virulence that of systemic isolates, and also found an association C. parapsilosis accounts for a significant proportion of between relative cell surface hydrophobicity and adhe- nosocomial infections, with an increasing prevalence. sion to acrylic surfaces. The high adherence to human As with other Candida species, invasion of C. parapsilo- buccal epithelial cells noted among certain of the sis can result in severe disease, particularly in hosts with C. parapsilosis isolates used in this study might be attrib- a suppressed immune system. For the development of uted to variation in strains and culture conditions, or more effective containment measures it is necessary to aggregation among yeast cells, but implies the potential understand the mechanisms that underlie pathogenic- for colonization of mucosal surfaces, possibly equal to ity. The lack of knowledge of virulence factors that play that of C. albicans (Panagoda et al. 2001). a role in the pathogenicity of C. parapsilosis may in part de Bernardis et al. (1999) found isolates from blood be due to the exclusive use of type-collection strains in and skin adhered about equally to plastic, but that most experiments (Cassone et al. 1995). The paucity of greater adhesion to plastic was found among iso- data on clinical isolates needs to be corrected. lates showing a fringed colony morphology versus a We suspect that the lower virulence of C. parapsilosis nonfringed morphology. In addition, these authors

For personal use only. compared to C. albicans and some other non-albicans reported higher secreted aspartic protease (Sap) pro- Candida species is a reason for the lower mortality and duction among isolates from skin, which were better morbidity rates observed in adults and neonates (Faix able to cause experimental rat vaginitis than were low 1992; Sullivan et al. 1995; Weems 1992). Comparing Sap-producing fungemia isolates. However, the skin C. parapsilosis with C. albicans has made it possible to isolates were less virulent than were the blood isolates define some putative virulence factors. These virulence in a model of systemic infection in neutropenic mice factors, present in both species, include adherence to (De Bernardis et al. 1999). These data indicate that epithelial and endothelial cells, proteinase production different biotypes may thus differ in virulence. Sap (Cassone et al. 1987; Ross et al. 1990), pseudohypha enzymes are considered a putative virulence factor of C. formation (Sobel et al. 1984), phospholipase production albicans (Gokce et al. 2007; Naglik et al. 2004). They may (Ibrahim et al. 1995) and phenotypic switching (Soll have a role in disrupting mucosal surfaces or destroying 1992). host defense proteins. These enzymes also have been The lower virulence of C. parapsilosis compared strongly associated in superficial, but not with systemic to C. albicans can also be attributed to the lack of for- invasion, caused by C. parapsilosis (Cassone et al. 1995; Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 mation of hyphae. Most Candida species, including De Bernardis et al. 1999; Gokce et al. 2007). However, C. parapsilosis (Laffey & Butler 2005) exist as spherical to Dagdeviren et al. (2005) observed a higher production ovoid blastospores or yeast cells. Many Candida species of acid proteinase among blood isolates compared to are capable, to various degrees, of producing chains of non-blood isolates. A proteinase inhibitor can reduce elongated blastospores termed pseudohyphae, both in tissue damage due to this species (Gacser et al. 2007b). vivo, and under certain conditions, in vitro. The hyphal Although C. parapsilosis possesses fewer Sap enzymes forms are more difficult to ingest, and the cell walls may than C. albicans (De Bernardis et al. 1999), Lin et al. be more resistant to digestion. In addition, hyphal forms (1995) reported differences in proteinase activity have been defined as more adhesive than pseudohyphae within the major DNA groups of C.parapsilosis. Group I (Hostetter 1994). showed strong to moderately strong proteinase produc- The ability of a micro-organism to adhere to tion, whereas group II and III isolates had low protein- mucosal surfaces is the critical first step for successful ase activity. Candida parapsilosis: a review 293

One potential virulence factor for C. parapsilosis identified, smooth phenotypes produce the least bio- includes slime production. This is of special importance film. The molecular mechanisms that regulate pheno- for adhesion to foreign body material and in formation typic switching in C. parapsilosis are not yet understood of biofilms (microbial communities that are associated (Laffey & Butler 2005). with solid surfaces such as intravascular catheters) (Nett Another enzyme that seems to play an important et al. 2007), which results in the increase of catheter- role in the pathogenesis of C. parapsilosis is phos- related candidemia and antifungal resistance related to pholipase. This group of enzymes affect adhesion to catheter insertion (De Bernardis et al. 1999; Hawser & and penetration of host cells. Phospholipase activity Douglas 1994). The molecular mechanisms that regulate was detected in 51% of C. parapsilosis strains in a study biofilm development in C. parapsilosis is not yet under- done by Ghannoum et al. (2000). Dagdeviren et al. stood (Girmenia et al. 1996; Laffey & Butler 2005; Levy (2005) described phospholipase activity among 26% of et al. 1998; Viscoli et al. 1999), although quorum-sensing the blood isolates. As with C. albicans, C. parapsilosis mediated through farnesol has been implicated (Laffey isolated from blood cultures were found to be stronger & Butler 2005). phospholipase producers than isolates from other body Song et al. (2005) also observed differences in biofilm sites (Ibrahim et al. 1995). One study indicated no sta- formation among the three groups of C. parapsilosis. tistical difference between phospholipase production They only observed biofilm production among the and adherence, possibly due to the small sample size group I C. parapsilosis isolates, the group preferentially (Dagdeviren et al. 2005). associated with bloodstream isolates and those from The enzyme lipase seems to be another important healthcare workers. Kuhn et al. (Kuhn et al. 2004) also virulence factor. These enzymes affect adhesion and may indicated less biofilm production among non-group I deny the host nutrients. Gacser et al. (2007a) showed that strains, and reported a greater biofilm production by out- lipase inhibitors significantly reduce tissue damage dur- break isolates compared to sporadic isolates. Recently, ing infection of reconstituted human tissues. Recently, Melo et al. (2007) demonstrated biofilm production in Gacser et al. (2007b) studied targeted gene deletion on all three groups. Tavanti et al. (2007) reported no bio- the lipase genes CpLIP1 and CpLIP2. Their data support film production among C. orthopsilosis (former group II the idea that lipase, secreted by C. parapsilosis, is involved C. parapsilosis) and 95% of the C. metapsilosis (formerly in disease pathogenesis. Extracellular lipase proteins group III C. parapsilosis) were unable to produce bio- are important for optimal growth of C. parapsilosis in film. Differences in the results of the three studies are lipid solutions, such as lipid-rich total parenteral nutri-

For personal use only. likely due to differences in methods of inducing biofilm tion, frequently used for very low birth weight neonates. production and the quantification methods (Melo et al. Another finding of the study was the correlation between 2007). The failure to produce extracellular matrix could biofilm formation and lipase. Biofilm formation of the contribute to the lower frequency of group II and III C. parapsilosis lipase-negative mutant was decreased (C. orthopsilosis and C. metapsilosis) in the clinical set- dramatically (Gacser et al. 2007b). This enzyme seems to ting (Tavanti et al. 2007). Parenteral nutrition and high be involved in survival of C. parapsilosis after phagocyto- glucose environments seems to play a role promoting sis by macrophages. Lipase-negative mutants were more the development of biofilm production (Branchini et al. readily phagocytosed and killed by macrophages, com- 1994; Kuhn et al. 2004). Recently, Ruzicka et al. (2007) pared to the parental strain and reconstituted mutants described a discrepancy of biofilm production between (mutants of C. parapsilosis showing lipase activity). The C. parapsilosis blood isolates and C. parapsilosis isolated lipase –negative strain of C. parapsilosis was tested in a from the skin. Biofilm production was found among 59% murine intraperitoneal infection model and showed less of the bloodstream isolates and just 39% in those from virulence compared to the parental and reconstituted the skin. Studies also reported that biofilms can also strains (Gacser et al. 2007b). Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 reduce susceptibility to antifungal agents (Ruzicka et al. Cassone et al. (1995) reported that C. parapsilosis is 2007; Shin et al. 2002). markedly heterogeneous in experimental pathogenicity Although phenotypic switching was largely studied and made a ranking of biotype. They assessed the vari- in C. albicans, recently it was determined that pheno- ous differential characteristics of colony morphology typic switching does occur in C. parapsilosis (Enger et al. (morphotype), resistance to various chemicals (resisto- 2001; Lott et al. 1993). This specific phenotypic instabil- type), and correlated these with virulence in a systemic ity allows strains to switch colony phenotype without murine infection model. These authors were able to affecting the identifiable genotype (Fidel et al. 1999; place isolates into groups on the basis of these traits, Soll 1992). Laffey & Butler (2005) found a correlation in although virulence in murine models showed a wide phenotypic switching and biofilm formation. The con- range within a group. In addition, these authors found centric phenotype generates up to twofold more biofilm no correlation of virulence in systemic infection with than crepe or crater phenotypes. Of the four phenotypes Sap production (Cassone et al. 1995). 294 van Asbeck et al.

Gacser et al. (2007a) investigated pathogenicity of pathogenic fungi, such as C. albicans, Blastomyces der- different C. parapsilosis strains in vitro using reconsti- matitidis and Paracoccidioides brasiliensis (Brummer tuted human epidermal and oral tissues. Reconstituted et al. 1991). The mechanism of killing C. parapsilosis epidermal human tissues are extremely useful for mod- by peritoneal macrophages, activated in vitro by eling host interactions with C. parapsilosis and studying lymphokines or recombinant gamma-interferon was virulence factors of this organism (Gacser et al. 2007a). studied by Brummer et al. (Brummer & Stevens 1989). Their results showed that C. orthopsilosis caused dam- They observed killing of C. parapsilosis by non-acti- age similar to C. parapsilosis, while C. metapsilosis was vated peritoneal macrophages. Superoxide dismutase less virulent. blocked and dimethyl sulfoxide partially blocked this Earlier studies on pathogenicity may have been killing, which suggested a mechanism depending on confusing because C. parapsilosis is a group of three the presence of superoxide anion is involved in the sibling species, as we now know. Thus comparisons of killing of C. parapsilosis by macrophages. Killing by traits may have been across species lines rather than activated macrophages was not inhibited by super- within a single species. Since we are now able to dis- oxide dismutase or dimethyl sulfoxide, suggesting tinguish these 3 species, it will be important for future that activated macrophages probably depend on the studies first to identify the organism to species level, so myeloperoxidase systems. In addition, Brummer et al. that the ­appropriate comparisons can be made. Host- (1991) observed no inhibition of killing of C. parapsi- parasite interaction studies will benefit by recognizing losis by the macrophages by the use of cycloheximide the genetic diversity of strains. Extensive genetic studies and hydrocortisone. (microarrays, the whole genome sequence) may make Takoa et al. (1996) examined the role of reactive oxy- it possible to define the virulence factors and the- ris gen metabolites in phagocytosis and killing by murine ing importance of C. parapsilosis makes these studies peritoneal macrophages incubated with C. parapsilosis, necessary. In addition, there is a need for models that by the use of a fluorochromatic vital staining technique. enable the study of interaction of this fungus in human The relative contribution of reactive oxygen metabolites, tissue, because of the rising importance of C. parapsilo- depending on NADPH oxidase or xanthine oxidase, sis among humans. was determined using selective inhibition of each of these enzyme systems. Generation of reactive oxygen metabolites by xanthine oxidase and NADPH oxidase- Host Response ­dependent pathways were found to be important for

For personal use only. Important to the relative virulence of C. parapsilosis is the phagocytic killing by murine peritoneal macrophages. host response to infections caused by C. parapsilosis. In Although there is a difference in pathogenicity of contrast to the vast body of work that has been described the species C. albicans and C. parapsilosis, Marodi on host defense against C. albicans, little is known about et al. (1991b) found no difference in the biochemical specific host defense mechanisms against C. parapsi- basis of phagocytosis by human monocytes or mono- losis. C. parapsilosis has been described as a relatively cyte derived macrophages between these two Candida low-grade pathogen for humans. However, infections species. In a separate study, C. parapsilosis was killed and death due to C. parapsilosis have increased steadily significantly better by human monocytes than was during the last decade, particularly among immuno- C. albicans; however monocyte derived macrophages compromised adults, but are also common in the non- did not require the yeast to be opsonized, and killed neutropenic hosts (i.e., premature infants and surgical both species to an equivalent extent (Marodi et al. patients). The differences in pathogenicity in different 1991a). The greater killing of C. parapsilosis by mono- host groups indicate that some level of host defense cytes may be due to the sensitivity of the yeast to does indeed exist. Better understanding of the mecha- toxic oxygen metabolites, hypochlorite, etc., which Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 nisms of host defense against C. parapsilosis may enable is required for the killing of Candida species (Marodi us to support or deploy these mechanisms against this et al. 1991a). In addition, opsonization was required opportunistic pathogen and improve treatment (Marodi for phagocytosis by monocytes for both C. albicans and et al. 1991b). C. parapsilosis, and used both the classical pathway Mononuclear phagocytes, macrophages and poly- and alternative pathway (Marodi et al. 1991b). Potoka morphonuclear leukocytes (PMN) have been studied et al. (1998) studied phagocytosis and phagocytic kill- and shown to be a critical component of host defense ing of C. parapsilosis by rat Kupffer cell alone and by that protects against candidemia and candidiasis Kupffer cells in coculture with hepatic endothelial (Aybay & Imir 1996; Marodi et al. 1991a; Marodi cell-enriched fraction of non-parenchymal cells. They et al. 1991b; Roilides et al. 1995a; Takao et al. 1996; also reported both the NAPD oxidase and the xanthine Vecchiarelli et al. 1985). C. parapsilosis is not as diffi- oxidase dependent pathways are important in Kupffer cult for macrophages to kill compared to several other cell killing of C. parapsilosis. Candida parapsilosis: a review 295

PMNs damage pseudohyphae, the invasive form of receptor may play a role in the clearance of Candida Candida species, by attachment and secretion of oxi- in opsonin-poor conditions, especially by macro- dative burst metabolites (Roilides et al. 1995a, Roilides phages. High avidity binding was shown between MBL et al. 1995b). Candida species differ in resistance to kill- and C. parapsilosis (van Asbeck et al. 2008c). MBL ing by PMNs. Roilides et al. (1995a) showed that non- increased the deposition of C4 and C3b, and enhanced opsonized pseudohyphae of C. parapsilosis were more the uptake of C. parapsilosis by neutrophils. Recently, resistant to PMN induced damage than were C. albicans Zhang et al. (2006) demonstrated a protective role for or C. tropicalis; GM-CSF and interferon-gamma sig- human antimannan antibody-mediated immunity nificantly enhanced the killing activity of PMN against and of murine antimannan antibody-mediated immu- C. parapsilosis. Possibly these differences in theCandida nity against experimental murine systemic candidiasis species susceptibility to PMNs may contribute to host due to C. albicans. Furthermore, these authors dem- susceptibility to infection (Roilides et al. 1995a). onstrated a mannan epitope, M1g1, which is common However, Lyman and Walsh (1994) obtained a similar to Candida spp., including C. parapsilosis (Zhang percentage of phagocytosis by PMN of serum-opsonized et al. 2006). These data are suggestive that antimannan C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata. antibodies, while protective against C. albicans infec- Vecchiarelli et al. (1985) showed equal killing of Candida tion, might also be protective against infection due to species by murine PMN and bone marrow cells, how- C. parapsilosis. ever C. guilliermondii, C. krusei, and C. parapsilosis were killed by these phagocytic cells more rapidly and Animal models at significantly lower effector to target ratio compared to C. albicans, C. tropicalis, and C. viswanathii. Experimental animal models are a critical component Cytokines, such as granulocyte-macrophage of understanding the pathogenesis and host resistance ­colony-stimulating factor (GM-CFS) and interferon-γ, to infection with Candida spp., as well as to develop- enhance the ability of phagocytic cells to damage or kill ment of more efficacious antifungal therapies (Capilla Candida cells (Roilides et al. 1995a). GM-CSF has the abil- et al. 2007). There has been very little development of ity to affect monocyte complement production (Hogasen animal models of C. parapsilosis, despite the emerging et al. 1995). Hogasen et al. (1995) determined the release of importance of C. parapsilosis infections, both systemic GM-CSF by monocytes after exposure to differentCandida and mucosal. Those models that have been developed species and compared the stimulation of production of have included mucosal models in mouse and rat (oral

For personal use only. complement components C3 and factor B by monocytes. or vaginal), and systemic murine models in normal or C. albicans, C. tropicalis, and C. parapsilosis were the more immunocompromised animals. In various experimental effective inducers of C3, factor B and GM-GSF production models, C. parapsilosis has been shown to be less patho- compared to C. krusei, T. glabrata (C. glabrata), C. kefyr, genic than Candida albicans and other Candida species C. guilliermondii, and T. candida (Hogasen et al. 1995). (Bistoni et al. 1984, Edwards et al. 1977; Howlett 1976). Hogasen et al. (1995) concluded that monocyte responses However, animal models have been used to examine dif- are associated with specific yeast species, related to patho- ferent aspects of infection due to C. parapsilosis and for genicity, and may explain predilection of some yeasts for preclinical antifungal trials. particular underlying diseases. The major components of the cell wall of Candida Mucosal models yeast are mannan, an α-linked polymer of mannose; glucan, a β-linked branched chain polysaccharide of In humans, C. parapsilosis has been associated most glucose; and chitin, a cellulose-like biopolymer con- often with vaginal or gastrointestinal colonization and sisting predominantly of N-acetyl-D-glucosamine disease and much less frequently with oral mucosal dis- Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 (Zhang et al. 2006). Mannose binding lectin (MBL), ease (Weems 1992). Several models of mucosal infection produced in the (human) liver is an important com- have been developed. ponent of innate immunity (serum) (Jack & Turner In an early study, Howlett et al. (1976) described 2003). Candida mannan is a likely target for MBL the varying abilities of five different Candida species binding (Lillegard et al. 2006). Mannose binding pro- to invade the orthokeratinized mucosa from the dorsal tein binds to carbohydrate structures on microbial surface of neonatal rat tongue, reflecting their different surfaces, leading to direct killing via complement acti- degree of pathogenicity. C. parapsilosis showed only vation or via enzymes linked to MBL, or via enhanc- slight invasion of the connective tissue, compared to ing phagocytosis by acting as an opsonin or chemo- C. albicans, which was the only species able to invade tactic factor (Ip & Lau 2004; Brummer & Stevens, in all the tissues present. The keratin layer of the rat tongue press). Opsonin-independent phagocytosis could mucosa appeared to act as a barrier to invasion of be blocked by mannan, suggesting the mannose the underlying epithelium by anything but a virulent 296 van Asbeck et al.

species. These data appear to correlate with the relative was unable to cause disease in either normal or cyclo- infrequency of C. parapsilosis as a cause of oral mucosal phosphamide immunosuppressed mice. In contrast, disease. Arendrup et al. (2002) using immunocompetent mice in Mellado et al. (2000) used adult mice given tetracy- a similar study, reported C. parapsilosis did show some cline and glucose and intragastric inoculation of yeasts virulence, with parameters such as weight loss, kidney to model gut colonization and described the virulence weight, inflammation and infection and number of eyes difference among species. C. parapsilosis showed per- infected. Like C. krusei and C. guilliermondii, C. parap- sistent colonisation but lacked the capacity for systemic silosis showed less virulence compared to the ­species spread from the gut tissues, whereas C. albicans did dis- C. albicans, C. tropicalis, C. glabrata, C. kefyr, and seminate from the gut. C. lusitaniae. In other studies, Andriole and Hasenclever de Bernardis et al. (1999) have described the impor- (1962) found mortality of diabetic mice infected with tance and increase of C. parapsilosis vaginal infections, C. albicans, C. tropicalis, or C. parapsilosis. which emphasize the need for vaginal models of C. par- A recent report of Nett et al. (2007) proposed β-1,3 apsilosis. de Bernardis et al. (1989a) developed an estro- glucan as a marker for C. albicans, C. parapsilosis, and gen-dependent rat vaginitis model for C. parapsilosis. C. glabrata biofilm using a central venous catheter In those studies one isolate was found to cause vaginitis (CVC) biofilm rat model. This model closely mimics a similar in extent to a C. albicans isolate, whereas two patient with CVC infection. This model has been used for other isolates of C. parapsilosis were unable to cause diagnostic purposes, where animals with experimental vaginitis in the rat model. Thus, differences in patho- CVC infection showed significantly higher serum levels genic potential were demonstrated among different iso- of β-1,3 glucan in C. parapsilosis and C. albicans biofilm lates of C. parapsilosis. In further studies using this same infections, compared with a model of systemic disease model, they suggested that C. parapsilosis is a true cause using tail-vein infection, representing disseminated or of human vaginitis (de Bernardis et al. 1989b). nonbiofilm disease. Although in humans C. parapsilosis is associated with endophthalmitis Edwards et al. (1977) were unable to Systemic models recover C. parapsilosis from the eyes in a rabbit model The association of C. parapsilosis with indwelling of haematogenous Candida endopthalmitis. They stud- catheters and fungemia underscores the importance ied ocular pathogenicities of species of Candida (e.g., of systemic models of infection due to this organism. C. krusei, C. parapsilosis, C. guilliermondii, C. tropicalis,

For personal use only. Murine models have been established in normal or C. stellateoidea, and C. albicans) and found a relative immunosuppressed mice by intravenous inoculation resistance of ocular tissues to haematogenous Candida of the organism. Mortality and fungal burden in the infections with species other than C. albicans. Thus, this organs are followed as parameters of disease severity. model would not appear useful for the study of endoph- Cassone et al. (1995) used normal or neutropenic mice thalmitis due to C. parapsilosis. to study systemic models for pathogenicity of different An alternative nonmammalian model has been C. parapsilosis isolates (blood, vaginal and environ- described by Chamilos et al. (2006b), who developed a mental). They found a range of virulence by the isolates model of candidiasis of Toll (Tl)-deficient Drosophila including one incapable of causing lethality in the neu- melanogaster. In agreement with mammalian animal tropenic model. Interestingly, and unlike the results of model studies, C. parapsilosis was less virulent than other authors, they found no correlation between Sap C. albicans when injected into Tl mutant flies. This alter- and pathogeneicity in the systemic infection models native model using D. melanogaster is promising for (Cassone et al. 1995). In further studies, this group large-scale studies of virulence mechanisms of candi- examined the pathogenicity of skin and blood isolates diasis (Chamilos et al. 2006b). Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 of C. parapsilosis, showing that the skin isolates did not cause disease in the systemic model, whereas some of the blood isolates were highly virulent (de Bernardis Antifungal susceptibility and therapy et al. 1999). Although both the organism and the host determine relative virulence of a pathogen, there are Antifungal susceptibility also differences of virulence among different strains of C. parapsilosis (Cassone et al. 1995). Widespread use of antifungal agents could be an expla- Systemic murine models have also been used to nation for the emergence of the more resistant non-albi- compare virulence among species of Candida. Bistoni cans species of Candida (Pfaller et al. 1995). Low levels et al. (1984) used cyclophosphamide immunodepressed of azole resistance in vitro have been observed for C. mice and normal mice to study pathogenicity of differ- parapsilosis, suggesting that the emergence of this spe- ent Candida species and reported that C. parapsilosis cies may be influenced by one or more confounding risk Candida parapsilosis: a review 297

factors in contrast to selection of species, such as C. gla- The emergence of yeast species with decreased sus- brata and C. krusei, which are much less susceptible to ceptibility to contemporary antifungal regimens dem- azole drugs (Kao et al. 1999). Identification of Candida onstrates the need for new antifungal agents (Capoor species and antifungal susceptibility provide important et al. 2005, Nguyen et al. 1996). The echinocandin information for the development of recommendations class of antifungals offers an alternative to the stand- for empirical antifungal therapy and can affect thera- ard regimens of azole or polyene agents and provides peutic choices (Fluckiger et al. 2006; Krcmery & Barnes additional advantages of reduced toxicity (Messer et al. 2002; Pfaller & Diekema 2002; Pfaller et al. 2002). In 2004). Caspofungin, micafungin and anidulafungin, addition, antifungal resistance surveillance programs echinocandin antifungal agents, compromise cell wall provide important information for the development of structural integrity through non-competitive inhibi- recommendations for empirical antifungal therapy and tion of the synthesis of 1,3-ß-D-glucan (Cappelletty for the design of programs for the control of antifungal & Eiselstein-McKitrick 2007; Denning 2003; Pfaller resistance (Pfaller & Diekema 2002). et al. 2006b). Compared to other Candida species, C. parapsilosis isolates are quite susceptible to C. parapsilosis tends to be associated with a higher MIC most systemic antifungal agents including polyenes of echinocandins (Cappelletty & Eiselstein-McKitrick (amphotericin B) and azoles (fluconazole, ketocona- 2007; Fleck et al. 2007; Laverdiere et al. 2007; Marco et al. zole, itraconazole, voriconazole, and posaconazole) 1998; Messer et al. 2004; Nakamura & Takahashi 2006; (Fluckiger et al. 2006; Mokaddas et al. 2007; Nakamura Ostrosky-Zeichner et al. 2003; Pfaller 2004; Pfaller et al. & Takahashi 2006; Ostrosky-Zeichner et al. 2003; 2005a; Pfaller et al. 2006a; Pfaller et al. 2006b; Reboli Pappas et al. 2004; Pfaller et al. 2002; Pfaller et al. et al. 2007). The meaning of these higher MICs is still 2005c; Pfaller et al. 2000; Pfaller et al. 1995; Rex et al. being investigated, but changes in the glucan synthase 1995; Weems 1992). Bille and Glauser (1997) tested subunit Fks1 might explain the reduced activity of echi- 30 isolates of C. parapsilosis, Laverdiere et al. (2007) nocandins against C. parapsilosis (Park et al. 2005; Reboli tested 14, and Fleck et al. (2007) tested 19 isolates; all et al. 2007). A recent report indicated the C. parapsilo- were susceptible to fluconazole and amphothericin B. sis complex has a naturally occurring polymorphism However, Seidenfeld et al. (1983) reported tolerance to resulting in the substitution of alanine at position 660 amphotericin B in C. parapsilosis, with minimal fun- for a conserved proline, which is present in other fungal gicidal concentrations more than 32-fold higher than Fks1 (Garcia-Effron et al. 2008). The unique mitochon- the MIC. Resistance to amphotericin has been noted drial respiratory network of C. parapsilosis might play

For personal use only. (Ostrosky-Zeichner et al. 2003). an important role for its decreased susceptibility to the Global surveillance studies, reported by Pfaller et al. echinocandins (Chamilos et al. 2006a). Chamilos et al. (Pfaller & Diekema 2004), indicated that reduced sus- (2006a) observed a decrease in caspofungin MICs after ceptibility to fluconazole is uncommon among blood- simultaneous inhibition of all respiratory pathways. stream isolates of C. parapsilosis, most frequent in From early studies, anidulafungin was demonstrated surgical ICU’s (Pfaller et al. 2008b). Similarly, Sarvikivi to have a minimal inhibitory concentration range for et al. (2005) observed fluconazole resistance in only one 90% of C. parapsilosis strains [MIC90] of <2-4 mg/L C. parapsilosis isolate during a 10-year period of fluco- (Arevalo et al. 2003; Marco et al. 2003; Marco et al. 1998; nazole prophylaxis and Kovacicova et al. (2000) reported Ostrosky-Zeichner et al. 2003; Pfaller et al. 1997). Marco, resistance in only two strains of C. parapsilosis, over a et al. (1998) reported a discrepancy between caspofun- period of 3 years. However, in addition to fluconazole gin and anidulafungin susceptibility for C. parapsilosis. resistance, resistance to itraconazole and voriconazole Anidulafungin showed less activity against C. parapsi- has been noted (Arias et al. 1994; Ostrosky-Zeichner losis than did caspofungin (MIC90, >2 versus 1 µg/mL). et al. 2003; Pfaller et al. 2007). Messer, et al. (2004) reported only 36% of 106 C. parap- Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 In an experimental study, Segal et al. (1975) described silosis strains tested were inhibited by anidulafungin the development of resistance to flucytosine by 23% at < 1 mg/L; however, nearly all isolates were inhibited of strains of C. parapsilosis. However, in the European at ≤ 4 mg/L. Reboli et al. (2007) directly compared the Confederation of Medical Microbiology (ECMM) sur- efficacy of anidulafungin with that of fluconazole for the vey of candidemia in Italy, only one of the 99 isolates of treatment of candidemia and other forms of invasive C. parapsilosis tested showed resistance to flucytosine candidiasis. In that study, anidulafungin showed higher (Tortorano et al. 2003). Lin et al. (1995) showed a dif- MICs for C. parapsilosis compared to other species of ference in susceptibility to flucytosine between group Candida, and patients with a C. parapsilosis infection I and II isolates of C. parapsilosis, with a tendency for treated with fluconazole showed a somewhat better increased resistance to flucytosine among the group II response rate compared to anidulafungin. However, isolates. the absolute difference in rate of successful response against C. parapsilosis was not significant. Recently, a 298 van Asbeck et al.

prospective sentinel surveillance determined the in vitro Paradoxical growth of some C. albicans isolates was activity of all three echinocandins against 5346 invasive observed in high concentrations of caspofungin (i.e., isolates of Candida, 14% consisting of C. parapsilosis those above the minimal inhibitory concentration) from 90 medical centers worldwide from 2001 to 2003. C. (Stevens et al. 2004, Stevens et al. 2005). The effect parapsilosis showed less susceptibility to all three agents was very reproducible, but re-test of cells growing at in each of the four regions, compared to C. albicans, high concentrations showed the parental phenotype C. glabrata, C. tropicalis, C. krusei and C. kefyr (Pfaller (paradoxical effect again), not resistance development. et al. 2008a). Chamilos et al. (2007) recently reported this phenom- For antifungal susceptibility testing it is important enon also among the other echinocandins, anidulafun- to identify the organism to species level, so that appro- gin, and micafungin in Candida species. Paradoxical priate comparisons can be made. Differences in anti- growth was seen in 90% of isolates (n = 10) of C. parap- fungal susceptibility might be explained by compari- silosis tested against caspofungin. However, no para- son of traits and mechanistic pathways across species doxical growth of C. parapsilosis was observed with ani- lines rather than within a single species. Recently, our dulafungin or micafungin. We (van Asbeck et al. 2008b) laboratory determined the susceptibility patterns of the studied paradoxical growth among the closely related strongly related species C. parapsilosis sensu stricto (for- species C. parapsilosis sensu stricto, C. orthopsilosis, and merly C. parapsilosis group I), C. orthopsilosis (formerly C. metapsilosis. Thirty-seven percent of the C. parapsi- C. parapsilosis group II), and C. metapsilosis (formerly losis sensu stricto isolates tested displayed paradoxical C. parapsilosis group III) to fluconazole, caspofungin growth in caspofungin. Despite close similarities among and anidulafungin (van Asbeck et al. 2008b). C. parap- sibling species, only C. parapsilosis sensu stricto seemed silosis sensu stricto had significantly higher caspofun- to have a high capability to avoid caspofungin inhibition. gin and anidulafungin MICs than C. orthopsilosis or Melo et al. (2007) indicated paradoxical growth was more C. metapsilosis. C. metapsilosis was the least susceptible common in Candida cells grown as biofilms, compared of the species to fluconazole. This observation showed to planktonic growth. All 3 species in the C. parapsilosis us that significant differences in drug susceptibility family demonstrated paradoxical growth in biofilms, occur among the sibling species. In addition, C. parap- and the paradoxical growth was more prominent in bio- silosis sensu stricto was significantly more susceptible films. Those cells demonstrating the paradoxical effect to caspofungin than anidulafungin. Gomez-Lopez et al. appear to be more resistant to host defenses (van Asbeck (2008) studied the susceptibility profile of C. orthopsi- et al. 2009), possibly related to cell wall changes (Stevens

For personal use only. losis and C. metapsilosis, which were highly susceptible et al. 2006), and thus this phenomenon may prove to be to all antifungals tested in this study (amphotericin B, a factor in poor therapeutic response to echinocandins flucytosine, fluconazole, voriconazole, ravuconazole, in some infections with this organism. Animal model posaconazole, caspofungin, micafungin, and ani- studies with Candida have not shown a consistent rela- dulafungin). C. orthopsilosis and C. metapsilosis were tionship of the paradoxical effect in vitro with in vivo more susceptible to amphotericin B and echinocand- resistance, though a “flattening” of the in vivo clearance ins, although no significant conclusions could be made despite increasing doses could be an in vivo expression because few isolates were tested. There was a trend for of the effect (Clemons, et al. 2006). C. parapsilosis sensu stricto and C. orthopsilosis to be Unconventional drug development pathways have more susceptible to caspofungin than the other two included inhibitors of aspartic proteinases, as several echinocandins, consistent with our significant differ- known antiretroviral protease inhibitors have this prop- ences for the former (van Asbeck et al. 2008b), and erty, and congeners may be developed that could be prior studies of the C. parapsilosis family (Marco et al. useful in arresting fungal pathogenesis. 1998; Pfaller et al. 2006a; Pfaller et al. 2006b). Others Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 (Lockhart et al. 2008a) have also reported echinoc- Preclinical antifungal drug trials andin MICs higher for C. parapsilosis sensu stricto than the sister species, also true for amphotericin B. Animal models provide a rapid way to test experimental Tavanti et al. (2007) determined susceptibility pat- therapies or examine approved drugs for new indica- terns of amphotericin B, ketoconazole, voriconazole tions (Capilla et al. 2007). Few preclinical trial data for and caspofungin for C. orthopsilosis. Only one strain infections due to C. parapsilosis have been published. showed resistance to flucytosine and was dose-de- Longman et al. (1990) described the efficacy of flucona- pendently susceptible to itraconazole. No resistance zole for therapy, as well for prophylaxis, of endocarditis to caspofungin was found. In biofilms, C. parapsilosis due to C. albicans and C. parapsilosis in a rabbit model. MICs to azoles rise, whereas echinocandin susceptibil- Therapeutically, 14 doses of fluconazole eradicated car- ity is similar to that for planktonic growth (Katragkou diac vegetations of C. parapsilosis and a two-dose pro- et al. 2008). phylactic regimen prevented experimental endocarditis Candida parapsilosis: a review 299

by C. parapsilosis and C. albicans. Similarly, Witt et al. this species might respond less readily to this antifun- (1993) used a rabbit model of Candida endocarditis gal drug. (both C. parapsilosis and C. tropicalis) and reported Candidemia and acute hematogenously disseminated amphotericin B or fluconazole effective therapeutically; candidiasis caused by C. parapsilosis may be treated prophylactic efficacy of fluconazole and amphotericin B with amphotericin B deoxycholate (0.6 mg/kg per day), has also been demonstrated in the same model (Bayer fluconazole (6 mg/kg per day) or caspofungin (70 mg et al. 1996). loading dose followed by 50 mg/day) (Pappas et al. Barchiesi et al. (2006) observed in a neutropenic 2004). Therapy for candidemia should be continue for murine model of systemic candidiasis the efficacy 2 weeks after the last positive blood culture results and of caspofungin against different Candida species. resolution of symptoms and signs (Pappas et al. 2004). Depending on the isolate tested, mice infected with C. In situations involving slime producing organisms, such parapsilosis required relatively high drug doses of caspo- as vascular catheter related infection, the organism is fungin, 1 and/or 5 mg/kg/day to show efficacy. More difficult to eradicate using antifungal therapy alone, recently, Barchiesi et al. (2007) described the efficacy of but several studies recommend removal of the infecting combination therapy and obtained synergistic interac- device to prevent invasive mycoses and their complica- tion of caspofungin and amphothericin B against C. par- tions (Nakamura & Takahashi 2006; Pfaller et al. 1995). apsilosis tested in the same murine model. Other combi- When feasible, it may prove useful in initial manage- nation studies using amphotericin B and the monoclonal ment to remove indwelling catheters, which is likely to antibody to heat shock protein 90, Mycograb, have been particularly affect the prevalence of secondary infec- done in a systemic murine model and demonstrated no tions caused by C. parapsilosis (Nakamura & Takahashi enhanced efficacy of the combination in reduction of 2006). This maneuver needs to be studied in randomized fungal burden due to C. parapsilosis, in contrast to sig- trials. nificant enhancement of efficacy against C. albicans, C. Very low birth weight neonates and premature krusei, or C. glabrata (Matthews et al. 2003). Additional neonates with disseminated cutaneous neonatal can- studies of the efficacy of various antifungal drugs alone didiasis who are at risk for developing acute dissemi- or in combination will be required in the future. nated candidiasis should be considered for systemic As a result of the data with the echinocandins and in therapy, as is the approach in those with disseminated particular caspofungin, it is not clear consequently that visceral candidiasis. Little information on pharma- these should be the drugs of first choice for treating infec- cokinetics and response rates is available for this group

For personal use only. tions with this organism. Whether the higher MICs for of patients. However, amphothericin B deoxycholate caspofungin will affect clinical outcomes is unknown. In appears to be first choice in treatment, primarily due vivo human data do not clearly yet correlate with the in to the lack of experience with other antifungal agents vitro data for the echinocandins for C. parapsilosis, and (Pappas et al. 2004). Fluconazole may be used as a still support the efficacy of echinocandins for invasive second line agent for very low birth weight neonates candidemia (Safdar et al. 2002). and premature neonates with disseminated cutane- ous neonatal candidiasis who are at risk for developing acute disseminated candidiasis (Pappas et al. 2004). Treatment Although prevention of nosocomial fungal infections Mora-Duarte et al. (2002) performed a double-blind in premature infants is desirable, long-term use of flu- trial to compare caspofungin with amphothericin B conazole may lead to the emergence of resistance in deoxycholate for the primary treatment of invasive C. parapsilosis. Thus, fluconazole prophylaxis should candidiasis. C. parapsilosis caused only 19% of cases be undertaken with caution (Chapman 2007; Sarvikivi of fungemia in the caspofungin-treated group in this et al. 2005; Yoder et al. 2004). Very low birth weight Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 study, but was associated with 42% of cases in the sub- children, during the first six weeks of life, have an set of patients with persistent fungemia. Conversely, increased risk for candidemia caused by C. parapsilosis the species distribution in cases of persistent fungemia (Kaufman et al. 2001). Prevention of fungal colonization in the amphotericin B-treated group more closely par- and invasive infections by fluconazole prophylaxis has alleled the overall distribution of infecting species in all been shown effective in these infants (Kaufman et al. types of fungemia. The overall rate of favorable response 2001; Kicklighter et al. 2001). In neonates, Krcmery for C. parapsilosis was similar for caspofungin versus et al. (2001) reported a better outcome and less mor- amphotericin B, 70% versus 65% (2002). Treatment tality for breakthrough fungemias (fungemias which failures for caspofungin were most commonly from occurred during fluconazole therapy), compared to blood. This suggested that caspofungin may be used non-breakthrough fungemias. Although not much is successfully for treatment of C. parapsilosis fungemia, described about caspofungin treatment in neonates, but physicians should be aware of the possibility that Odio et al. (2004) showed successful treatment with 300 van Asbeck et al.

caspofungin of invasive candidiasis due to C. albi- and are recommended therapy by the IDSA (Pappas cans, C. parapsilosis, C. tropicalis, and C. glabrata, et al. 2004). Both agents are also effective for peritoneal in neonates who were resistant to or intolerant of candidiasis caused by C. parapsilosis (Chen et al. 2004, amphotericin B. Caspofungin might be an appropri- Kaitwatcharachai 2002). Chen et al. (2004) observed in ate alternative for treatment of invasive candidiasis in a retrospective study comparable efficacy of treatment premature neonates when there is decreased response with fluconazole alone to intraperitoneal amphotericin to the other antifungals such as amphothericin B or B alone or intraperitoneal amphotericin B combined fluconazole (Odio et al. 2004). with intravenous fluconazole. However, combination No treatment for Candida endocarditis has been for- of fluconazole and amphotericin B should be used mally tested in prospective randomized controlled studies cautiously, because of the possibility of antagonism (Garzoni et al. 2007). Combined medical and surgical ther- (Kaitwatcharachai 2002). Recently Chen et al. (2006) apy appears to be the best treatment for Candida endocar- showed that when fluconazole is used as initial ther- ditis. The Infectious Diseases Society of America (IDSA) apy, complications are significantly higher in patients and another study recommend surgical valve replace- with C. parapsilosis peritonitis than patients with peri- ment of either native valve or prosthetic valve infections tonitis caused by other species. In disease associated (Garzoni et al. 2007; Pappas et al. 2004). Amphotericin B with catheters used for peritoneal dialysis, early cath- deoxycholate was the most frequently prescribed antifun- eter removal is often required for successful therapy for gal drug in previous studies, then flucytosine and flucona- peritoneal candidiasis (Bren 1998; Kaitwatcharachai zole (Garzoni et al. 2007). Rapid and efficient treatment 2002; Pappas et al. 2004). is important, because this may improve the outcome of In general, management of Candida arthritis depends fungal endocarditis (Garzoni et al. 2007). on site of infection (Pappas et al. 2004). Intravenous Endophthalmitis caused by Candida species can be amphotericin B and fluconazole have been used for treated with amphotericin B (Pappas et al. 2004; Stern medical therapy of Candida arthritis (Brooks & Pupparo et al. 1985). A good alternative choice of treatment is 1998; Pappas et al. 2004). Arthritis caused by Candida fluconazole and it is particularly useful for follow-up species that involves prosthetic joints requires removal therapy (Pappas et al. 2004; Torres Perez et al. 2004). of the primary prosthesis to eradicate the infection In addition, fluconazole may be effective for the treat- (Brooks & Pupparo 1998). ment associated with an intraocular lens implant, Vaginal candidiasis due to C. parapsilosis is cleared however, removal of the implant is required (Kauffman from subsequent culture relatively easily (Nyirjesy et al.

For personal use only. et al. 1993). Since treatment can save vision, evidence 2005). Short-courses of treatment such as topical boric acid of intraocular infection should be sought as soon as (600 mg/day for 14 days), oral fluconazole 200 mg twice possible (Feman et al. 2002). Marangon et al. (2004) weekly for 1 month or topical antimycotic therapy, such showed sensitivity to amphotericin B, fluconazole, itra- as topical flucytosine, successfully clear the vaginitis infec- conazole, ketoconazole, flucytosine, and voriconazole tions caused by C. parapsilosis (Nyirjesy et al. 2005; Pappas of Candida isolates, including C. albicans, C. parap- et al. 2004). Other choices in treatment are “over the coun- silosis, and C. tropicalis recovered from patients with ter” clotrimazole, buconazole, or miconazole as vaginal endophthalmitis. Voriconazole may play a role in the applications (Nyirjesy et al. 2005, Pappas et al. 2004). therapeutic ­management of endophthalmitis caused Not much about treatment of candiduria due to by Candida ­species, because of the highest potency C. parapsilosis has been described. Following the IDSA of this drug against Candida species (Marangon et al. guidelines (Pappas et al. 2004), candiduria should be 2004). Vitrectomy appears to be an important therapeu- treated in symptomatic patients, neutropenic patients, tic maneuver in treatment of endophthalmitis (Stern very low birth weight infants, patients with renal allo- et al. 1985; Stevens 1983). All patients with candidemia grafts and patients undergoing urologic manipulation. Critical Reviews in Microbiology Downloaded from informahealthcare.com by The University of Manchester on 11/20/12 should undergo an ophthalmological examination to Therapy with fluconazole (oral or intravenous), ampho- exclude the possibility of endophthalmitis. Therapy for tericin B (intravenous), or flucytosine (oral) are effective endophthalmitis should be continued until complete and require 7–14 day courses to be successful. When resolution of visible disease (Pappas et al. 2004). possible, removal of a urinary catheter might be helpful. Peritonitis caused by C. parapsilosis should be Itraconazole, fluconazole, and terbinafine are effec- treated more aggressively than other Candida spp, tive in treating onychomycosis due to Candida species since C. parapsilosis peritonitis has a higher compli- (Gupta & Shear 2000). The IDSA indicated itraconazole cation rate (complications such as abscess formation to be the most appropriate treatment for onychomy- and persistent peritonitis after catheter removal) than cosis caused by Candida species (Pappas et al. 2004). other Candida spp. (Chen et al. 2006). Intravenous Terbinafine may be more effective against C. parap- amphotericin B, oral or intravenous fluconazole silosis compared to C. albicans (Gupta & Shear 2000). remain the drugs of choice for peritoneal candidiasis Higher doses of drugs and longer duration of therapy are Candida parapsilosis: a review 301

required for onychomycosis caused by Candida species Arevalo, M P, Carrillo–Munoz, A J, Salgado, J, Cardenes, D, Brio, S, than is the case for nail infections caused by dermato- Quindos, G, and Espinel–Ingroff, A 2003. Antifungal activity of the echinocandin anidulafungin (VER002, LY–303366). against phytes (Gupta & Shear 2000). yeast pathogens: a comparative study with M27–A microdilu- Treatment of otomycosis involves local debride- tion method. J Antimicrob Chemother 51, 163–6. ment and topical antifungal therapy for up to 14 weeks, Arias, A, Arevalo, M P, Andreu, A, Rodriguez, C, and Sierra, A 1994. In vitro susceptibility of 545 isolates of Candida spp to four anti- depending on the depth and extent of infection. fungal agents. Mycoses 37, 285–9. Ashford, B 1928. Certain conditions of the gastrointestinal tract in Puerto Rico and their relation to tropical sprue. Am J Trop Med Hyg 8, 507–38. Summary and conclusions Aybay, C, and Imir, T 1996. 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